Acute renal failure (ARF) is the most common renal disease requiring hospitalization and is associated with significant mortality. It is increasingly recognized that ARF predisposes the kidney to long-term complications in surviving patients. We have previously shown evidence for peritubular capillary dropout following ARF and hypothesized that this is an important factor predisposing progressive renal disease. Work from the previous project period has shown that following recovery from ARF, Na-diet predisposes hypertension and hastens chronic kidney disease. While vascular dropout may contribute to this alteration in function, it is additionally hypothesized, in the current application that I/R-induced alterations in vascular reactivity and fibroblast deposition may also contribute to alterations in renal function leading to CRF.
Specific aim 1 will evaluate alterations in vascular reactivity and define the role of oxidant stress systems in the alterations of renal hemodynamics and sodium excretion. These studies will focus on the post-ischemic response to perfusion pressure, angiotensin II and determine the mechanism of protection by VEGF. The second specific aim will explore vascular dropout directly;the studies will evaluate the proliferative potential of endothelial progenitor cells in the kidney and evaluate the efficacy of endothelial progenitor cells (EPC) in restoring renal vascular function following injury, with and without angiogenic growth factor therapy. We will compare EPCs derived from either bone-marrow or from vessel walls, determine if the source of EPC affects long-term renal vascular function. Studies will determine if EPC cells incorporate to promote new blood vessel formation, affect renal blood flow under the influence of angiogenic growth factors, and evaluate long-term renal function and progression of CRF. The final specific aim (#3) is designed to define the relative impact of interstitial myofibroblast vs. blood vessel dropout on progression to CRF following ARF. These studies will utilize transgenic mice harboring fibroblast specific expression of the HSV thymidine kinase gene, to deplete (myo) fibroblasts following the induction of ARF. These studies are designed to separate the influence of interstitial cells vs. peritubular capillary loss in predisposing long term changes in renal function and hemodynamics.

Public Health Relevance

Acute renal failure (ARF) is the most common renal disease requiring hospitalization is associated with significant mortality. As the number of patients that survive ARF is increasing, it is becoming recognized that ARF predisposes secondary chronic kidney disease and hypertension. The work in this application will utilize rodent models of ARF that develop secondary chronic kidney disease. The overall goal is to gain an understanding as to how acute injury changes kidney structure and function so as to develop into chronic kidney disease. The acquisition of this information is required to design effective strategies for this increasingly apparent health problem.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Kimmel, Paul
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Indiana University-Purdue University at Indianapolis
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United States
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